tbuckley/cabot-search huggingface dataset:
Alterations in fecal β-defensin-3 secretion as a marker of instability of the gut microbiota
Authors: Zarwa Saqib, Giada De Palma, Jun Lu, Michael Surette, Premysl Bercik, Stephen Michael Collins
Journal: Gut Microbes (2023)

Compositional changes in the microbiota (dysbiosis) may be a basis for Irritable Bowel Syndrome (IBS), but biomarkers are currently unavailable to direct microbiota-directed therapy. We therefore examined whether changes in fecal β-defensin could be a marker of dysbiosis in a murine model. Experimental dysbiosis was induced using four interventions relevant to IBS: a mix of antimicrobials, westernized diets (high-fat/high-sugar and high salt diets), or mild restraint stress. Fecal mouse β-defensin-3 and 16S rRNA-based microbiome profiles were assessed at baseline and during and following these interventions. Each intervention, except for mild restraint stress, altered compositional and diversity profiles of the microbiota. Exposure to antimicrobials or a high-fat/high-sugar diet, but not mild restraint stress, resulted in decreased fecal β-defensin-3 compared to baseline. In contrast, exposure to the high salt diet increased β-defensin-3 compared to baseline. Mice exposed to the mix of antimicrobials showed the largest compositional changes and the most significant correlations between β-defensin-3 levels and bacterial diversity. The high salt diet was also associated with significant correlations between changes in β-defensin-3 and bacterial diversity, and this was not accompanied by discernible inflammatory changes in the host. Thus, dietary change or antimicrobial exposure, both recognized factors in IBS exacerbations, induced marked dysbiosis that was accompanied by changes in fecal β-defensin-3 levels. We propose that serial monitoring of fecal β-defensins may serve as a marker of dysbiosis and help identify those IBS patients who may benefit from microbiota-directed therapeutic interventions.
Histone Methyltransferase NSD2 Activates PKCα to Drive Metabolic Reprogramming and Lenalidomide Resistance in Multiple Myeloma
Authors: Phyllis S.Y. Chong, Jing-Yuan Chooi, Julia S.L. Lim, Aaron C.Y. Leow, Sabrina Hui Min Toh, Irfan Azaman, Mun Yee Koh, Phaik Ju Teoh, Tuan Zea Tan, Tae-Hoon Chung, Wee Joo Chng
Journal: Cancer Research (2023)

Multiple myeloma cells undergo metabolic reprogramming in response to the hypoxic and nutrient-deprived bone marrow microenvironment. Primary oncogenes in recurrent translocations might be able to drive metabolic heterogeneity to survive the microenvironment that can present new vulnerabilities for therapeutic targeting. t(4;14) translocation leads to the universal overexpression of histone methyltransferase NSD2 that promotes plasma cell transformation through a global increase in H3K36me2. Here, we identified PKCα as an epigenetic target that contributes to the oncogenic potential of NSD2. RNA sequencing of t(4;14) multiple myeloma cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCα, and the glycolytic gene, hexokinase 2 (HK2), was transcriptionally regulated by PKCα in a PI3K/Akt-dependent manner. Loss of PKCα displaced mitochondria-bound HK2 and reversed sensitivity to the glycolytic inhibitor 3-bromopyruvate. In addition, the perturbation of glycolytic flux led to a metabolic shift to a less energetic state and decreased ATP production. Metabolomics analysis indicated lactate as a differential metabolite associated with PKCα. As a result, PKCα conferred resistance to the immunomodulatory drugs (IMiD) lenalidomide in a cereblon-independent manner and could be phenocopied by either overexpression of HK2 or direct supplementation of lactate. Clinically, t(4;14) patients had elevated plasma lactate levels and did not benefit from lenalidomide-based regimens. Altogether, this study provides insights into the epigenetic-metabolism cross-talk in multiple myeloma and highlights the opportunity for therapeutic intervention that leverages the distinct metabolic program in t(4;14) myeloma.Aberrant glycolysis driven by NSD2-mediated upregulation of PKCα can be therapeutically exploited using metabolic inhibitors with lactate as a biomarker to identify high-risk patients who exhibit poor response towards IMiD-based regimens.
GTP Cyclohydrolase Drives Breast Cancer Development and Promotes EMT in an Enzyme-Independent Manner
Authors: Zijing Wang, Nan Zhang, Miao Zhang, Yao Jiang, Aik Seng Ng, Esther Bridges, Wei Zhang, Xin Zeng, Qi Luo, Jiabien Liang, Balázs Győrffy, Philip Hublitz, Zhu Liang, Roman Fischer, David Kerr, Adrian L. Harris, Shijie Cai
Journal: Cancer Research (2023)

Abstract GTP cyclohydrolase (GCH1) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. The catalysis of BH4 biosynthesis is tightly regulated for physiological neurotransmission, inflammation, and vascular tone. Paradoxically, BH4 has emerged as an oncometabolite regulating tumor growth, but the effects on tumor development remain controversial. Here, we found that GCH1 potentiated the growth of triple-negative breast cancer (TNBC) and HER2+ breast cancer and transformed nontumor breast epithelial cells. Independent of BH4 production, GCH1 protein induced epithelial-to-mesenchymal transition by binding to vimentin (Vim), which was mediated by HSP90. Conversely, GCH1 ablation impaired tumor growth, suppressed Vim in TNBC, and inhibited EGFR/ERK signaling while activating the p53 pathway in estrogen receptor–positive tumor cells. GCH1 deficiency increases tumor cell sensitivity to HSP90 inhibition and endocrine treatments. In addition, high GCH1 correlated with poor breast cancer survival. Together, this study reveals an enzyme-independent oncogenic role of GCH1, presenting it as a potential target for therapeutic development. Significance: GTP cyclohydrolase functions as an oncogene in breast cancer and binds vimentin to induce epithelial-to-mesenchymal transition independently of its enzyme activity, which confers targetable vulnerabilities for developing breast cancer treatment strategies.
Trends and Seasonality of Emergency Department Visits and Hospitalizations for Suicidality Among Children and Adolescents in the US from 2016 to 2021
Authors: Youngran Kim, Trudy Millard Krause, Scott D. Lane
Journal: JAMA Network Open (2023)

The detection of seasonal patterns in suicidality should be of interest to clinicians and US public health officials, as intervention efforts can benefit by targeting periods of heightened risk.To examine recent trends in suicidality rates, quantify the seasonality in suicidality, and demonstrate the disrupted seasonality patterns during the spring 2020 COVID-19-related school closures among US children and adolescents.This population-based, descriptive cross-sectional study used administrative claims data from Optum's deidentifed Clinformatics Data Mart Database. Participants included children aged 10 to 12 years and adolescents aged 13 to 18 years who were commercially insured from January 1, 2016, to December 31, 2021. Statistical analysis was conducted between April and November 2022.Month of the year and COVID-19 pandemic.Rates and seasonal patterns of emergency department (ED) visits and hospitalizations for suicidality.The analysis included 73 123 ED visits and hospitalizations for suicidality reported between 2016 and 2021. Among these events, 66.1% were reported for females, and the mean (SD) age at the time of the event was 15.4 (2.0) years. The mean annual incidence of ED visits and hospitalizations for suicidality was 964 per 100 000 children and adolescents (95% CI, 956-972 per 100 000), which increased from 760 per 100 000 (95% CI, 745-775 per 100 000) in 2016 to 1006 per 100 000 (95% CI, 988-10 024 per 100 000) in 2019, with a temporary decrease to 942 per 100 000 (95% CI, 924-960 per 100 000) in 2020 and a subsequent increase to 1160 per 100 000 (95% CI, 1140-1181 per 100 000) in 2021. Compared with January, seasonal patterns showed peaks in April (incidence rate ratio [IRR], 1.15 [95% CI, 1.11-1.19]) and October (IRR, 1.24 [95% CI, 1.19-1.29]) and a nadir in July (IRR, 0.63 [95% CI, 0.61-0.66]) during pre-COVID-19 years and 2021. However, during the spring of 2020, which coincided with school closures, seasonal patterns were disrupted and April and May exhibited the lowest rates.The findings of this study indicated the presence of seasonal patterns and an observed unexpected decrease in suicidality among children and adolescents after COVID-19-related school closures in March 2020, which suggest a potential association between suicidality and the school calendar.
Disease risk and healthcare utilization among ancestrally diverse groups in the Los Angeles region
Authors: Christa Caggiano, Arya Boudaie, Ruhollah Shemirani, Joel Mefford, Ella Petter, Alec Chiu, Defne Ercelen, Rosemary He, Daniel Tward, Kimberly C. Paul, Timothy S. Chang, Bogdan Pasaniuc, Eimear E. Kenny, Jonathan A. Shortt, Christopher R. Gignoux, Brunilda Balliu, Valerie A. Arboleda, Gillian Belbin, Noah Zaitlen
Journal: Nature Medicine (2023)
Association Between Markers of Structural Racism and Mass Shooting Events in Major US Cities
Authors: Michael Ghio, John Tyler Simpson, Ayman Ali, Julia M. Fleckman, Katherine P. Theall, Joseph I. Constans, Danielle Tatum, Patrick R. McGrew, Juan Duchesne, Sharven Taghavi
Journal: JAMA Surgery (2023)

Importance The root cause of mass shooting events (MSEs) and the populations most affected by them are poorly understood. Objective To examine the association between structural racism and mass shootings in major metropolitan cities in the United States. Design, Setting, and Participants This cross-sectional study of MSEs in the 51 largest metropolitan statistical areas (MSAs) in the United States analyzes population-based data from 2015 to 2019 and the Gun Violence Archive. The data analysis was performed from February 2021 to January 2022. Exposure Shooting event where 4 or more people not including the shooter were injured or killed. Main Outcome and Measures MSE incidence and markers of structural racism from demographic data, Gini income coefficient, Black-White segregation index, and violent crime rate. Results There were 865 MSEs across all 51 MSAs from 2015 to 2019 with a total of 3968 injuries and 828 fatalities. Higher segregation index (ρ = 0.46, P = .003) was associated with MSE incidence (adjusted per 100 000 population) using Spearman ρ analysis. Percentage of the MSA population comprising Black individuals (ρ = 0.76, P &amp;amp;lt; .001), children in a single-parent household (ρ = 0.44, P &amp;amp;lt; .001), and violent crime rate (ρ = 0.34, P = .03) were other variables associated with MSEs. On linear regression, structural racism, as measured by percentage of the MSA population comprising Black individuals, was associated with MSEs (β = 0.10; 95% CI, 0.05 to 0.14; P &amp;amp;lt; .001). Segregation index (β = 0.02, 95% CI, −0.03 to 0.06; P = .53), children in a single-parent household (β = −0.04, 95% CI, −0.11 to 0.04; P = .28), and Gini income coefficient (β = −1.02; 95% CI, −11.97 to 9.93; P = .93) were not associated with MSEs on linear regression. Conclusions and Relevance This study found that major US cities with higher populations of Black individuals are more likely to be affected by MSEs, suggesting that structural racism may have a role in their incidence. Public health initiatives aiming to prevent MSEs should target factors associated with structural racism to address gun violence.
Racial and Ethnic Diversity in Medical School Admissions in Canada
Authors: Ye Bin Shin, Amanda Stojcevski, Taylore Dupuis-Miller, Amrit Kirpalani
Journal: JAMA Network Open (2023)

Importance Medical schools promote admission pathways as well as diversity and inclusivity to prospective students who are underrepresented in medicine (UIM) primarily via their websites. Research from organizational structures supports the use of instrumental values (which focus on behavior and core beliefs), rather than terminal values (which focus on the end goal), to promote diversity. Objective To characterize the use of instrumental and terminal values to promote institutional diversity and inclusivity on Canadian medical school websites. Design, Setting, and Participants This qualitative study analyzed the contents and themes of Canadian medical school websites based on a theoretical value framework and an organizational diversity management framework. A literature review was conducted to explore the use of instrumental and terminal values in promoting diversity and inclusivity, and a codebook was created that outlined the characteristics of these values. The content of all application pathway websites for UIM applicants to all Canadian medical schools was coded between July and August 2022. Main Outcomes and Measures Use of terminal vs instrumental values across the UIM-targeted admission websites of medical schools. Results Twenty-two websites for 17 Canadian medical schools were included. Content on most of these websites promoted diversity in response to government policies or public accountability and often supported a dominant culture while treating diversity as an exception. The use of terminal rather than instrumental values was also more prominent on websites that targeted Indigenous prospective students compared with Black prospective students and applicants with lower socioeconomic status (11 [50%] websites vs 5 [23%] and 4 [18%] websites). Instrumental values, although seldom used, promoted diversity as a means to improve health care and training for all students in a program. Conclusions and Relevance Results of this qualitative study suggested that medical schools in Canada promoted diversity and inclusivity to prospective students primarily as an end goal rather than as a core value. Medical schools should highlight the benefits of diverse lived experiences and reinforce their commitment to diversity and inclusion by aligning their website content with their ongoing work in this area.
Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses
Authors: Thomas D. Als, Mitja I. Kurki, Jakob Grove, Georgios Voloudakis, Karen Therrien, Elisa Tasanko, Trine Tollerup Nielsen, Joonas Naamanka, Kumar Veerapen, Daniel F. Levey, Jaroslav Bendl, Jonas Bybjerg-Grauholm, Biao Zeng, Ditte Demontis, Anders Rosengren, Georgios Athanasiadis, Marie Bækved-Hansen, Per Qvist, G. Bragi Walters, Thorgeir Thorgeirsson, Hreinn Stefánsson, Katherine L. Musliner, Veera M. Rajagopal, Leila Farajzadeh, Janne Thirstrup, Bjarni J. Vilhjálmsson, John J. McGrath, Manuel Mattheisen, Sandra Meier, Esben Agerbo, Kári Stefánsson, Merete Nordentoft, Thomas Werge, David M. Hougaard, Preben B. Mortensen, Murray B. Stein, Joel Gelernter, Iiris Hovatta, Panos Roussos, Mark J. Daly, Ole Mors, Aarno Palotie, Anders D. Børglum
Journal: Nature Medicine (2023)
Clinical development of mRNA therapies against solid tumors
Authors: Dawei Wu, Lingfeng Hu, Xin Wang, Yue Yu, Shuo-Peng Jia, Hui-Yao Huang, Zi-Wei Li, Jin-Feng Ma, Hai-Bo Zhu, Yu Tang, Ning Li
Journal: Journal of Hematology & Oncology (2023)

Abstract The mRNA-based therapeutics have become the hot spot of biopharmaceutical industries in recent years. The landscape of this area is expanding from infectious disease to cancer, which needs to be summarized to provide data supports for industries and research institutions. Based on the Trialtrove database, a total of 108 clinical trials from 1999 to 2021 were retrospectively analyzed. We have demonstrated that the clinical development of mRNA therapies against solid tumors is still at an early stage. There are evolutions in delivery systems from the dendritic cell to the lipid-based platform and in encoding strategies from the fixed tumor antigens to the personalized neoantigens. The adjuvant or maintenance therapy and the combination treatment with checkpoint inhibitors are becoming the major clinical development orientation.
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Authors: Chun-Chan Zheng, Xiao-Xuan Chen, Rui-Tao Zou, Gui-Yue Cai, Rong-Yi Chen, X.-X Zheng, R.-Y Chen, X.-X Chen, Cai Zou, Rong-Yi Chen
Journal: JAMA Dermatology (2023)

Caryn B. C. Cobb, BA; Candrice R. Heath, MD; Angel S. Byrd, MD, PhD; Lynn J. McKinley-Grant, MD, MA; Valerie Callender, MD; Adewole S. Adamson, MD, MPP; Stafford Brown III, MS; Seemal R. Desai, MD; Donald A. Glass II, MD, PhD; Tarannum Jaleel, MD, MHSc; Ginette A. Okoye, MD; Susan C. Taylor, MD; Valerie M. Harvey, MD, MPH
Learning Individual Survival Models from PanCancer Whole Transcriptome Data
Authors: Neeraj Kumar, Daniel Skubleny, Michael Parkes, Ruchika Verma, Sacha Davis, Luke Kumar, Amira Aissiou, Russell Greiner
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Personalized medicine attempts to predict survival time for each patient, based on their individual tumor molecular profile. We investigate whether our survival learner in combination with a dimension reduction method can produce useful survival estimates for a variety of patients with cancer. Experimental Design: This article provides a method that learns a model for predicting the survival time for individual patients with cancer from the PanCancer Atlas: given the (16,335 dimensional) gene expression profiles from 10,173 patients, each having one of 33 cancers, this method uses unsupervised nonnegative matrix factorization (NMF) to reexpress the gene expression data for each patient in terms of 100 learned NMF factors. It then feeds these 100 factors into the Multi-Task Logistic Regression (MTLR) learner to produce cancer-specific models for each of 20 cancers (with &amp;gt;50 uncensored instances); this produces “individual survival distributions” (ISD), which provide survival probabilities at each future time for each individual patient, which provides a patient's risk score and estimated survival time. Results: Our NMF-MTLR concordance indices outperformed the VAECox benchmark by 14.9% overall. We achieved optimal survival prediction using pan-cancer NMF in combination with cancer-specific MTLR models. We provide biological interpretation of the NMF model and clinical implications of ISDs for prognosis and therapeutic response prediction. Conclusions: NMF-MTLR provides many benefits over other models: superior model discrimination, superior calibration, meaningful survival time estimates, and accurate probabilistic estimates of survival over time for each individual patient. We advocate for the adoption of these cancer survival models in clinical and research settings.
An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles
Authors: Robert S Bresalier, Carlo Senore, Graeme P Young, James Allison, Robert Benamouzig, Sally Benton, Patrick M M Bossuyt, Luis Caro, Beatriz Carvalho, Han-Mo Chiu, Veerle M H Coupé, Willemijn de Klaver, Clasine Maria de Klerk, Evelien Dekker, Sunil Dolwani, Callum G Fraser, William Grady, Lydia Guittet, Samir Gupta, Stephen P Halloran, Ulrike Haug, Geir Hoff, Steven Itzkowitz, Tim Kortlever, Anastasios Koulaouzidis, Uri Ladabaum, Beatrice Lauby-Secretan, Mārcis Leja, Bernard Levin, Theodore Robert Levin, Finlay Macrae, Gerrit A Meijer, Joshua Melson, Colm O'Morain, Susan Parry, Linda Rabeneck, David F Ransohoff, Roque Sáenz, Hiroshi Saito, Silvia Sanduleanu-Dascalescu, Robert E Schoen, Kevin Selby, Harminder Singh, Robert J C Steele, Joseph J Y Sung, Erin Leigh Symonds, Sidney J Winawer
Journal: Gut (2023)

Objective New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. Design A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. Results Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test’s ability to discriminate between CRC and non-cancer states ( phase I ), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations ( phase II ). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. Conclusion New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.
Errors in Figure 2 and Table 2 Footnotes
Journal: JAMA Dermatology (2023)

Eric L. Simpson, MD; Melinda Gooderham, MD; Andreas Wollenberg, MD; Stephan Weidinger, MD, PhD; April Armstrong, MD, MPH; Jennifer Soung, MD; Silvia Ferrucci, MD; Renata Gontijo Lima, MD; Michael M. Witte, PhD; Wen Xu, PhD; Hany ElMaraghy, MD; Chitra R. Natalie, MD; Evangeline Pierce, PhD; Andrew Blauvelt, MD, MBA; ADhere Investigators; Abel Jarell; Neil Sadick; Howard Sofen; Paul W Wallace; Jose M Carpio; David Greenstein; Angela Moore; Jose M Mendez; Scott T Guenthner; Wendy L McFalda; Vivian T Laquer; Seth Forman; Todd Schlesinger; Andrew Blauvelt; Jeffrey J Crowley; Ricardo Tan; Francis J Averill; Rosalyn E George; Eddie Armas; Benjamin Lockshin; Jennifer Soung; Walter K Nahm; Alison A Ehrlich; Sunil S Dhawan; Eric L Simpson; Steve Sitar; Jerry Bagel; Phoebe Rich; Bruce Torkan; David F Fivenson; Jamie D Weisman; Melody L Stone; April Armstrong; Mirwais Saifi; Brad P Glick; Melinda Gooderham; Isaiah Day; Lorne Albrecht; Marni Wiseman; David Gratton; Chi-Ho Hong; Bernadetta Majorek-Olechowska; Adam Reich; Beata Krecisz; Irena Walecka-Herniczek; Jolanta Weglowska; Beata Bergler-Czop; Boguslawa Cimoszko; Kamila Padlewska; Maria Czubek; Andreas Pinter; Kristian Reich; Thomas Wildfeuer; Roland Aschoff
Positron emission tomography imaging of inflammation in diabetes mellitus
Authors: Neil J Craig, Marc R Dweck
Journal: Cardiovascular Research (2023)

Journal Article Positron emission tomography imaging of inflammation in diabetes mellitus Get access Neil J Craig, Neil J Craig Centre for Cardiovascular Sciences, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 6SB, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Marc R Dweck Marc R Dweck Centre for Cardiovascular Sciences, University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 6SB, UK Corresponding author. Tel: +44 781 361 9208, Email: marc.dweck@ed.ac.uk https://orcid.org/0000-0001-9847-5917 Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 119, Issue 10, August 2023, Pages 1887–1888, https://doi.org/10.1093/cvr/cvad109 Published: 18 July 2023 Article history Published: 18 July 2023 Corrected and typeset: 20 July 2023